EP0991627B1 - Pyrimidinone compounds, pharmaceutical compositions containing the compounds and the process for preparing the same - Google Patents

Pyrimidinone compounds, pharmaceutical compositions containing the compounds and the process for preparing the same Download PDF

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Publication number
EP0991627B1
EP0991627B1 EP99916058A EP99916058A EP0991627B1 EP 0991627 B1 EP0991627 B1 EP 0991627B1 EP 99916058 A EP99916058 A EP 99916058A EP 99916058 A EP99916058 A EP 99916058A EP 0991627 B1 EP0991627 B1 EP 0991627B1
Authority
EP
European Patent Office
Prior art keywords
methyl
compound
butyl
tetrazol
biphenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP99916058A
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German (de)
English (en)
French (fr)
Other versions
EP0991627A1 (en
Inventor
Jae-Hyoung Lee
Kyung-Jin Jang
Byoung-Wug Yoo
Ji-Han Kim
Jae-Seog Kang
Sang-Lin Kim
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Boryung Pharmaceutical Co Ltd
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Boryung Pharmaceutical Co Ltd
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Application filed by Boryung Pharmaceutical Co Ltd filed Critical Boryung Pharmaceutical Co Ltd
Publication of EP0991627A1 publication Critical patent/EP0991627A1/en
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Publication of EP0991627B1 publication Critical patent/EP0991627B1/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a novel pyrimidinone compounds and the pharmaceutically acceptable salts thereof.
  • This invention also relates to a process for preparing the novel pyrimidinone compounds and a pharmaceutical composition containing the pyrimidinone compounds.
  • Pyrimidinone derivatives according to this invention and the pharmaceutically acceptable salts thereof are useful as antagonists against angiotensin II, especially, in treatment of cardiovascular diseases caused by binding angiotensin II to its receptor.
  • Renin-angiotensin system plays a central role in the regulation of blood pressure in human body.
  • Angiotensin II consisting of eight amino acids, is produced through the cleavage of angiotensin I by angiotensin converting enzyme(ACE) localized on the arterial blood vessels of lung.
  • Angiotensin II interacts with specific receptors present in blood vessels, smooth muscle, kidney, and adrenal gland, to induce the blood pressure and the electrolyte concentration to increase.
  • novel pyrimidinone derivatives of thioamid and amidine which are superior to pyrimidinone derivatives disclosed in the prior art or the said imidazole derivatives in the activities and active time periods.
  • An object of the invention is to provide with novel pyrimidinone derivatives and the pharmaceutically acceptable salts thereof which inhibit the action of angiotensin II effectively with high activities.
  • the present invention provides with pyrimidinone derivatives and the pharmaceutically acceptable salts thereof having the general formula (I): wherein:
  • the pyrimidinone compounds according to the present invention and pharmaceutically acceptable salts thereof exhibit remarkable activities.
  • R 1 is ethyl, n-propyl, n-butyl, cyclopropyl, ethoxy or propoxy
  • R 2 is H, halogen or C 1 ⁇ C 4 normal or side chain alkyl
  • R 3 and R 4 are same or different H, methyl, ethyl, propyl or butyl , or R 3 and R 4 are together with N atom forming 4 to 8 membered heterocyclic ring, which can be further substituted with one or two substituents selected from the group consisting of cycloalkyl, aryl or arylalkyl, halogen, hydroxy, C 1 ⁇ C 4 alkoxy, amino, alkylamino, or dialkylamino (each alkyl residue having C 1 ⁇ C 5 ), C 1 ⁇ C 4 alkoxycarbonyl, carboxy and aminocarbonyl, and C 1 ⁇ C 4 normal or side chain alkyl wherein said heterocyclic ring can further include
  • the Pharmaceutically acceptable salts of the invention include inorganic salts obtainable by reacting corresponding pyrimidinone compounds (I) with hydroxides of alkali metal or alkaline earth metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide or magnesium hydroxide, potassium hydroxide, calcium hydroxide or magnesium hydroxide, carbonate of alkali metal or alkaline earth metals such as sodium carbonate, potassium carbonate, calcium carbonate or magnesium carbonate, or alcoholate of alkali metal or alkaline earth metals such as sodium, potassium, calcium or magnesium, and organic salts obtainable by reacting with organic amine in H 2 O, alcohols such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc., tetrahydrofuran, or the mixture thereof.
  • hydroxides of alkali metal or alkaline earth metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide or magnesium hydroxide, potassium hydroxide, calcium hydroxide or magnesium hydrox
  • the compound (I) can be prepared by reacting formula (I) of below-mentioned compound (II).
  • R 1 , R 2 , R 3 , R 4 , X, Z, m, and n have the meaning defined as above.
  • Starting materials of the compound of formula II may be prepared by the process which has been disclosed in the PCT application Laying-Open Publication No. WO96-08476 by the present inventors.
  • the compound of formula I, in which X is S may be easily prepared by reacting compound (II) with P 4 S 10 , bis(tricyclohexyltartar)sulfide or Lawesson's reagent in a dissolvent selected among benzen, dichioromethan or tetrahydrofuran.
  • Representative compounds of the invention are as follows, wherein name in the parentheses respectively after the compounds represent tentative name used through the specification.
  • a compound of formula I and the pharmaceutically acceptable salts thereof may be administered orally or parenterally in a conventional dosage from such as tablet, capsule, powder, troches, dry mixes, ointment, suspension or solution prepared according to conventional pharmaceutical practices.
  • the compounds of formula I, etc. can be administered at a dosage of from about 40mg/kg to about 100mg/kg preferably of body weight per day.
  • the compounds of the present invention have extremely low toxicity.
  • the LD 50 in mice is in excess of 5000mg/kg of body weight, as shown in the experimental test 2.
  • the femoral artery catheter was connected to a pressure transducer (COBE 041-500-508, USA) coupled to a polygraph (GRASS Model 7, USA) to monitor arterial blood pressure.
  • COBE 041-500-508, USA a pressure transducer
  • GASS Model 7, USA a polygraph
  • Angiotensin II 0.1 ⁇ g/kg was injected in the femoral vein three times during the control period.
  • Test compounds were then administered orally (p.o.) at a constant volume of 2ml/kg.
  • Angiotensin II challenges were repeated at set times thereafter.
  • ID 50 values the dose of test compound necessary to produce 50% inhibition of Angiotensin II-induced pressor response, were calculated from peak inhibition percentage with several doses of test compound.
  • COMPOUND NO. ID 50 (mg/kg, P.O.) Compound 1 >3.0 Compound 2 1.10 Compound 3 ⁇ 3.0 Compound 4 3.10 Compound 5 ⁇ 3.0 Compound 6 ⁇ 3.0 Compound 7 ⁇ 3.0 Compound 8 0.93 Compound 9 1.19
  • mice of ICR system which was distributed from Korean Laboratory Animal Center, were bred in a polycarbonate breeding box at a breeding environment of 23 ⁇ 1°C of temperature, 55 ⁇ 5% of humidity, 10-15 times/hr of evacuation, 12hr cycle of fluorescent light luminance, and 150-300 Lux of illumination.
  • mice After observing the mice for one week of acclimation breeding period, only normal mice were selected for laboratory work. The mice were fed with sterilized feed for laboratory animals, which was made by Cheil Jedang Co.,Ltd, and supplied with purified water to drink.
  • mice who were evaluated to be healthy, were weighed and divided into groups randomly. Individual identification of laboratory animals was performed by indumentum pigment display and tag display per breeding box.
  • body weight of the laboratory animals was in the range of 24-28g in case of male and in the range of 19-28g in case of female, respectively.
  • the laboratory animals were aged 6 weeks.
  • Preparation of the testing substances was dissolved in physiological saline before administration. Dose was calculated according to the body weight which was measured before administration and dispensed by oral administration to a mouse who was in abrosia for 18 hours before testing.
  • Administration group who was administered with testing substances, and the control group were weighed on the administration day, first, third, seventh, tenth and fourteenth days from the administration at a predetermined time for all animals who were alive.
  • tablets containing other compounds (2) to (14) of the invention were prepared (Examples 16 to 28).
  • COMPOSITION WEIGHT (mg) 1) Compound 1 40 2) Lactose 30 3) Corn Starch 100 4) Microcrystalline Cellulose 25 5) Magnesium Stearate 5 Total 200
  • capsules containing other compounds (2) to (14) of the invention were prepared (Examples 30 to 42).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cardiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP99916058A 1998-04-25 1999-04-26 Pyrimidinone compounds, pharmaceutical compositions containing the compounds and the process for preparing the same Expired - Lifetime EP0991627B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
KR1482198 1998-04-25
KR1019980014821A KR19990081093A (ko) 1998-04-25 1998-04-25 피리미디논 화합물, 이를 함유하는 약제학적 조성물 및 이의제조방법
PCT/KR1999/000198 WO1999055681A1 (en) 1998-04-25 1999-04-26 Pyrimidinone compounds, pharmaceutical compositions containing the compounds and the process for preparing the same

Publications (2)

Publication Number Publication Date
EP0991627A1 EP0991627A1 (en) 2000-04-12
EP0991627B1 true EP0991627B1 (en) 2003-07-02

Family

ID=19536698

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EP99916058A Expired - Lifetime EP0991627B1 (en) 1998-04-25 1999-04-26 Pyrimidinone compounds, pharmaceutical compositions containing the compounds and the process for preparing the same

Country Status (13)

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US (1) US6294542B1 (id)
EP (1) EP0991627B1 (id)
JP (1) JP3351539B2 (id)
KR (2) KR19990081093A (id)
CN (1) CN1195741C (id)
AU (1) AU753424B2 (id)
BR (1) BR9906373B1 (id)
CA (1) CA2295446C (id)
DE (1) DE69909209T2 (id)
ES (1) ES2209421T3 (id)
ID (1) ID29295A (id)
RU (1) RU2233278C9 (id)
WO (1) WO1999055681A1 (id)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100617953B1 (ko) * 2000-03-23 2006-08-30 보령제약 주식회사 피리미디논 화합물 및 이의 염의 제조방법
WO2003024956A1 (en) * 2001-09-21 2003-03-27 Boryung Pharmaceutical Co., Ltd. Method for preparing pyrimidinone compound and pharmaceutically acceptable salts thereof
KR100521980B1 (ko) * 2002-10-10 2005-10-17 보령제약 주식회사 피리미디논 화합물 및 이의 염의 삼수화물의 제조 방법
CN104610164B (zh) * 2010-01-21 2018-03-16 保宁制药株式会社 2‑(2‑正丁基‑4‑羟基‑6‑甲基‑嘧啶‑5‑基)‑n,n‑二甲基乙酰胺的制备方法
PE20141049A1 (es) * 2011-04-12 2014-09-05 Boryung Pharm Composicion farmaceutica antihipertensiva
KR101490329B1 (ko) * 2012-10-12 2015-02-04 보령제약 주식회사 피마살탄 포타슘염의 일수화물 결정, 그 제조방법, 및 그를 포함하는 약제학적 조성물
KR20170006938A (ko) 2015-07-10 2017-01-18 보령제약 주식회사 만성 신부전의 예방 또는 치료용 조성물
CN105061405A (zh) * 2015-08-04 2015-11-18 合肥创新医药技术有限公司 非马沙坦钾盐三水合物的制备方法
KR102233673B1 (ko) 2016-01-27 2021-03-30 보령제약 주식회사 당뇨병성 신장질환의 예방 또는 치료용 약학적 조성물
CN105837514B (zh) * 2016-01-29 2018-09-18 北京睿创康泰医药研究院有限公司 非马沙坦药物杂质的制备方法
WO2018002673A1 (en) 2016-07-01 2018-01-04 N4 Pharma Uk Limited Novel formulations of angiotensin ii receptor antagonists
KR101984121B1 (ko) * 2017-08-21 2019-05-30 보령제약 주식회사 피리미디논 유도체 화합물 및 이의 용도
KR102078691B1 (ko) 2017-11-30 2020-02-19 보령제약 주식회사 피마살탄을 포함하는 고체 분산체
KR102201396B1 (ko) 2017-11-30 2021-01-11 보령제약 주식회사 피마살탄을 포함하는 약학적 조성물
KR20200073676A (ko) 2018-12-14 2020-06-24 엠에프씨 주식회사 발사탄 및 사쿠비트릴을 포함하는 고체 분산체 및 이를 포함하는 약학 조성물 및 이의 제조 방법
CN109485640B (zh) * 2018-12-24 2021-03-26 合肥创新医药技术有限公司 一种非马沙坦杂质的制备方法
CN112876424B (zh) * 2019-11-29 2023-06-30 上海拓界生物医药科技有限公司 血管紧张素ii受体及内皮素受体双重拮抗剂
KR102221856B1 (ko) * 2020-10-12 2021-03-02 유니셀랩 주식회사 신규한 피마살탄 결정형의 다형체
KR20220154987A (ko) 2021-05-14 2022-11-22 주식회사 보령 허혈성 뇌졸중 또는 일과성 허혈 발작을 갖는 대상체에서의 혈압 조절을 위한 약학적 조성물
KR20220162456A (ko) 2021-06-01 2022-12-08 주식회사 보령 고혈압을 동반한 당뇨병성 신장질환의 예방 또는 치료용 약학적 조성물

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US5100897A (en) 1989-08-28 1992-03-31 Merck & Co., Inc. Substituted pyrimidinones as angiotensin ii antagonists
US5014228A (en) 1989-09-21 1991-05-07 Schlumberger Technologies, Inc. Method and apparatus for calibrating linear delay lines
JPH04120072A (ja) * 1990-09-11 1992-04-21 Meiji Seika Kaisha Ltd アンジオテンシン２拮抗性ピリミジン誘導体
EP0481614A1 (en) * 1990-10-01 1992-04-22 Merck & Co. Inc. Substituted pyridopyrimidinones and related heterocycles as angiotensin II antagonists
EP0550313A1 (fr) 1991-12-30 1993-07-07 Synthelabo Nouveaux dérivés de 2-(tétrazol-5-yl)-(1,1'-biphényle), leur préparation et leur utilisation comme intermédiaires de synthèse
FR2688505B1 (fr) * 1992-03-16 1994-05-06 Synthelabo Nouveau procede de preparation de 4-pyrimidinones.
FR2700543B1 (fr) * 1993-01-15 1995-03-17 Synthelabo Sels de dérivés de 4-pyrimidinone, leur préparation et leur application en thérapeutique.
JPH07157485A (ja) * 1993-12-02 1995-06-20 Nkk Corp 縮合ピリミジノン誘導体及びそれらを含有するアンジオテンシンｉｉ拮抗剤
KR100300566B1 (ko) * 1994-09-17 2001-11-22 조생현 피리미디논유도체와그의제조방법및용도

Also Published As

Publication number Publication date
CA2295446A1 (en) 1999-11-04
ES2209421T3 (es) 2004-06-16
ID29295A (id) 2001-08-16
DE69909209D1 (de) 2003-08-07
RU2233278C2 (ru) 2004-07-27
CN1195741C (zh) 2005-04-06
AU3443899A (en) 1999-11-16
WO1999055681A1 (en) 1999-11-04
EP0991627A1 (en) 2000-04-12
RU2233278C9 (ru) 2009-11-27
KR19990081093A (ko) 1999-11-15
US6294542B1 (en) 2001-09-25
CN1266428A (zh) 2000-09-13
JP2001508469A (ja) 2001-06-26
CA2295446C (en) 2009-01-06
AU753424B2 (en) 2002-10-17
BR9906373A (pt) 2000-07-11
KR20010013626A (ko) 2001-02-26
JP3351539B2 (ja) 2002-11-25
KR100354654B1 (ko) 2002-09-30
BR9906373B1 (pt) 2010-11-16
DE69909209T2 (de) 2004-06-03

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